With the research and training proposed in this application, I will build on my formal education in molecular and cellular biology and research in the neurobiology of mood disorders, to develop rare expertise understanding dietary components of mental illness. There is ample basic science evidence that diet and nutrition influence brain function and psychiatric illness. However, psychiatrists rarely explore nutritional issues in the clinic due to the relative lack of systematic clinical research. I aim to use the K01 award to develop translational research expertise in the role of dietary factors at the interface between mood and metabolism. The training component of this application includes mentored training in metabolomic sciences, clinical research in bipolar disorder, genetics, and biostatistics; as well as didactic training in human nutrition science, biostatistics, and the ethics of human research. The research component of this application focuses on a specific hypothesis regarding the role of essential fatty acids in bipolar disorder and integrates all aspects of the mentored and didactic training. Previous research implicates polyunsaturated fatty acids (PUFA) in bipolar disorder. Low tissue concentrations of omega-3 fatty acids associate with bipolar disorder, and several studies show that supplementing omega-3s may be efficacious in treating the disease. However, the data are confounded because the tissue ratio of omega-3s to omega-6s is also important, since these two classes of PUFA compete with each other and play many opposing physiological roles. Their tissue concentrations largely reflect the diet, however, allelic variation in genes that regulate lipid metabolism are also involved. Therefore, there is a diet by gene interaction in the control of PUFA profiles. Interestingly, one proposed mechanism of action for mood stabilizer medications used to treat bipolar disorder is the specific inhibition of turnover and downstream signaling of the omega-6, arachidonic acid, in neurons. Previous studies evaluating the efficacy of omega-3s in treating bipolar disorder, and on-going use of mood stabilizers, have not taken dietary or genetic factors relative to omega-6 activity into account. Therefore, this represents a new avenue for clinical research. High omega-6 tissue levels, especially those of arachidonic acid, may oppose the efficacy of omega-3 supplementation or mood stabilizer treatment approaches, yet this has not been evaluated. With the proposed research, we will evaluate the contribution of diet and genetic variants controlling PUFA profiles, to bipolar disorder etiology and treatment resistance. With the current award, I will train in human nutrition, metabolomics and clinical psychiatric research and apply the training to test a hypothesis for the role of a specific diet by gene interaction in bipolar disorder. I will emerge from this training as a competitive clinical researcher in a field that has a significant potential to impact current psychiatric practice by understanding complex dietary factors that influence mental health and disease. PUBLIC HEALTH RELEVANCE: The role of dietary factors in psychiatric illness etiology and treatment is not well understood, despite a large basic science literature implicating nutrients in the control of neurochemical circuits and brain function. The current proposal aims develop expertise in human nutrition at the interface between mood and metabolism and conduct clinical research studies to understand dietary factors in mental health.